Basis of Hormonal Contraception

Like the female hormonal methods that attempt to suppress ovularion, male hormonal methods are based on the suppression of hypothalamic gonadotropin-releasing hormone (GnRH) that in turn inhibits the secretion and production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). luteinizing-hormone normally stimulates the Leydig cells to secrete testosterone, resulting in a sufficiently high intratesricular testosterone concentration to maintain spermatogenesis. follicle-stimulating hormone, through its receptors on the Sertoli cells within the seminiferous tubules, stimulates and maintains spermatogenesis. In all currently tested male hormonal methods, total or near-total suppression of both luteinizing-hormone and follicle-stimulating hormone is required to produce the marked suppression of spermatogenesis required for azoospermia or near azoospermia. Selective suppression of follicle-stimulating hormone by follicle-stimulating hormone immunization has not resulted in the severe decrease in sperm production. Similarly, experiments involving follicle-stimulating hormone receptor mutations in both mice and men did not produce a severe and uniform suppression of spermatogenesis.

Because luteinizing-hormone suppression and the consequent marked reduction in endogenous testosterone production are necessary components of male hormonal contraceptive methods, androgen supplementation is thus required to prevent hypogonadism. Androgen activity is necessary for patients to maintain normal sexual function, mood, muscle, and bone mass. The regimens of hormonal male contraception that have been tested include androgens alone (testosterone alone) or androgens plus another gonadotropin suppressive agent such as progestin or a gonadotropin-releasing hormone antagonist (testosterone plus progestins). The details of the recent studies on various testosterone alone or testosterone plus progestins regimens have been reviewed. (For more information on the hormones of the male reproductive system, see site)

Mechanisms of Action of Male Hormonal Contraception

Studies indicate that hormonal male contraception relies on the marked suppression of follicle-stimulating hormone, luteinizing-hormone, and intratesticular testosterone. In the mature rat, intratesricular testosterone deprivation, achieved by treatment with a gonadotropin-releasing hormone antagonist or exogenous testosterone implants, caused stage- and cell-specific activation of germ-cell apoptosis, predominantly at stages VII and VIII of the rat spermatogenic cycle. The involvement of the intrinsic pathway signaling in male germ-cell apoptosis in rats after hormone deprivation has been demonstrated. The initiation of apoptosis is associated with a cell-type specific increase in the expression of the proapoptotic protein, Bax, involving only those germ cells undergoing apoptosis; this is accompanied by a marked decrease in levels of the antiapoptoric protein, Bcl-2. Other investigators have reported that failure of sperm release from the germinal epithelium may also contribute to decreased sperm output after follicle-stimulating hormone inhibition or testosterone suppression. The use of a gonadotropin-releasing hormone antagonist or testosterone implants in monkeys resulted in inhibition of spermiarion with a rapid and marked decrease in germ-cell development from type A pale spermatogonia and type B spermatogonia onward, demonstrating that suppression of follicle-stimulating hormone is essential to attain consistent azoospermia. Testicular samples obtained from human subjects participating in clinical trials of male contraceptive agents (testosterone alone or testosterone plus progestin) similarly showed a marked decrease in type B spermatogonia. Impairment of spermatogenesis from that stage onward and inhibition of spermiation were important determinants of sperm output. (For further information on spermatogenesis, see site)

Figure Male hormonal contraception and the hypothalamic-pituitary-testis axis.

Efficacy of Male Hormonal Contraception

To study whether hormonally induced azoospermia or severe oligospermia (arbitrarily defined as less than 3 million sperm cells / mL of ejaculate) has contraceptive efficacy, the World Health Organization conducted two pivotal studies in the 1990s. In the first study, when azoospermia was induced by exogenous administration of weekly testosterone enanthate injections, the contraceptive efficacy was 0.8 per 100 person-years. In the second study, when suppression of spermatogenesis reached severe oligospermia with exogenous testosterone enanthate injections in 357 couples, the contraceptive efficacy was 1.4 per 100 person-years. Four pregnancies occurred in the second study, with the pregnancy rate being proportional to the residual sperm concentration. This contraceptive efficacy rate is similar to those of currently available female methods of contraception such as injectables, pills, and patches. More recently, two studies demonstrated similar contraceptive efficacy utilizing undecanoate alone and testosterone pellets with depot medroxyprogesterone acetate injections.

Androgens-Alone Regimens

Androgens and Progestins

Table Androgen and Progestin Combinations lists the combination of androgens and progestins that have undergone testing in more recent clinical trials. Reviews of these androgen- and plus-progestin studies have been published. These include oral levonorgestrel and desogestrel, injectables such as depot medroxyprogesterone acetate and norethisterone enanthate, and implants of levonorgestrel and desogestrel [etonogestrel]. These studies, conducted in both Asian and non-Asian men, indicate that the addition of a progestin to an androgen induces more rapid suppression of spermatogenesis, with greater than 90% of non-Asian men becoming azoospermic with some combinations (e.g., norethisterone enanthate plus testosterone undecanoate, depot medroxyprogesterone acetate plus testosterone pellets, and oral desogestrel with testosterone enanthate). The addition of progestins primarily acts to suppress gonadotropin-releasing hormone and the gonadotropins, although recent studies suggest that progestins may also have direct actions on the tesris. Addition of androgenic oral progestins such as levonorgestrel and desogestrel results in weight gain and greater suppression of high-density lipoprotein cholesterol and serum sex hormone-binding globulin than androgen-alone regimens.

Table Androgen and Progestin Combinations

Progestins Androgens
Injectables
DMPA +Testosterone enanthate+Testosterone undecanoate (lntramuscular injection)

+Testosterone pellets

+19 nortestosterone

Norethisterone enanthate +Testosterone undecanoate (lntramuscular injection)
Oral
Levonorgestrel +Testosterone enanthate+Testosterone undecanoate (lntramuscular injection)

+Testosterone patch

+Dihydrotestosterone gel

+Testosterone pellets

Desogestrel +Testosterone enanthate+Testosterone pellets

+MENT

Implants
Etonogestrel +Testosterone pellets+Testosterone undecanoate (lntramuscular injection)
Levonorgestrel +Testosterone enanthate injections+Testosterone pellets

+Testosterone undecanoate (lntramuscular injection)

Agents with antiandrogen activity
Cyproterone acetate +Testosterone enanthate+Testosterone undecanoate oral

Abbreviations: DMPA, depot medroxyprogesterone acetate; METN,  7-alpha-methyl-19 nor-testosterone.

One of the most promising combinations may be that of testosterone undecanoate plus norethisterone enanthate, given as an injection every six to eight weeks. In studies involving a small number of men, this combination of steroids resulted in over 90% of men achieving azoospermia, with severe oligospermia in the remainder. testosterone undecanoate is also being studied in combination with etonogestrel implants as an injectable preparation given every 10 to 12 weeks, designed to release adequate etonogestrel for suppression of gonadotropins in men. Single or double etonogestrel implants are also being tested in combination with testosterone pellets and with METN (7-alpha-methyl-19 nor-testosterone) implants. levonorgestrel implants have also been tested with testosterone and METN implants.

All of these studies have the objective of developing either a practical bimonthly injectable or a yearly implant system for men. Although the oral progestins are very potent and active, at present, there is no oral testosterone preparation that can be used with these oral progestins. An orally active, potent androgen without significant adverse effects is yet to be developed for achieving the goal of having a male equivalent of the female “pill.” Combinations of androgen plus progestin in a trans-dermal application have not yet been tested.

Progestins with Antiandrogenic Activity

The progestin cyproterone acetate has antiandrogenic effects. A study with a small number of men showed that when cyproterone acetate was used in combination with testosterone enanthate, the resulting suppression was sufficient to induce azoospermia in all subjects. When testosterone enanthate injections were substituted with oral testosterone undecanoate, however, the suppression of spermatogenesis was incomplete.

Role of Androgens in Progestin-Androgen Combinations

When levonorgestrel implants were used in combination with transdermal testosterone patches, azoospermia occurred in about 25% of the men. This percentage was markedly increased when testosterone enanthate injections were administered with levonorgestrel implants. These studies indicate that the androgen component in the androgen-progestin combination plays an important role in the inhibition of gonadorropins and enhances the contraceptive efficacy of progestins in addition to providing androgen supplementation.

GnRH Antagonists and Androgens

Although gonadotropin-releasing hormone agonists are very safe, they fail to suppress luteinizing-hormone and follicle-stimulating hormone levels consistently enough to induce complete inhibition of spermatogenesis even with high doses or continuous infusions. In contrast, gonadotropin-releasing hormone antagonists are extremely effective in suppressing the secretion of both luteinizing-hormone and follicle-stimulating hormone as they completely block gonadotropin-releasing hormone action. In combination with androgens, gonadotropin-releasing hormone antagonists suppress sperm production to achieve azoospermia in most men. The earlier gonadotropin-releasing hormone antagonists, however, produced the unwelcome side effects of local skin reaction when administered subcutaneously. The recently synthesized gonadotropin-releasing hormone antagonist acyline, however, does not appear to have this problem, and when administered at a relatively high dose, it can maintain suppression of the gonadotropins for about 14 days. Currently, acyline is being developed for male contraception by the National Institutes of Health. Because gonadotropin-releasing hormone antagonists are expensive to synthesize, a more user-friendly, long-acting delivery system is also under development. Several pharmaceutical companies are also developing nonpepride antagonists via receptor drug modeling methods.

The potential for the oral activity of these agents may be a great contribution to the development of male contraceptive methods.

Maintenance of Spermatic Suppression with Androgens Alone

Another theoretical approach examines whether the gonadotropin-releasing hormone antagonist plus androgen-induced suppression of spermatogenesis can be maintained by androgens alone. If maintenance of suppression can indeed be achieved with androgens alone, this approach may offer considerable advantages in terms of less long-term steroid exposure for men and the overall economy of a treatment that only employs a single agent. Swerdloff et al. showed that when severe oligospermia is induced by a potent gonadotropin-releasing hormone antagonist (Nal-Glu Gonadotropin-Releasing Hormone) and testosterone enanthate injections, the suppression can be maintained for four months with testosterone enanthate injections alone. Other studies using 19 nor-testosterone alone, however, failed to maintain the suppression of spermatogenesis to azoospermia induced by the same regimen.

Reversibility of Hormonal Male Contraception

A recent integrated mulrivariate time-to-event analysis of data from individual participants in 30 studies published between 1990 and 2005 demonstrated full reversibility of male hormonal contraception within a predictable time course. The typical probability of recovery of 20,000,000 sperm / mL of semen was 67% within 6 months, 90% within 12 months, and 100% within 24 months.

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